12-117263909-A-G

Position:

• chr12-117263909-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000620.5(NOS1):​c.2202T>C​(p.Ile734=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,612,974 control chromosomes in the GnomAD database, including 412,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.75 (43283 hom., cov: 29)
  • Exomes 𝑓: 0.71 (368824 hom.)
• Consequence: NOS1 NM_000620.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.374

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-117263909-A-G is Benign according to our data. Variant chr12-117263909-A-G is described in ClinVar as [Benign]. Clinvar id is 3060480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.374 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.2202T>C	p.Ile734=	synonymous_variant	13/29	ENST00000317775.11
NOS1	NM_001204218.2	c.2202T>C	p.Ile734=	synonymous_variant	13/30
NOS1	NM_001204213.2	c.1194T>C	p.Ile398=	synonymous_variant	12/28
NOS1	NM_001204214.2	c.1194T>C	p.Ile398=	synonymous_variant	12/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.2202T>C	p.Ile734=	synonymous_variant	13/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.2202T>C	p.Ile734=	synonymous_variant	12/29	5
NOS1	ENST00000618760.4	c.2202T>C	p.Ile734=	synonymous_variant	13/30	5

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113472 AN: 151836 Hom.: 43234 Cov.: 29

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.739

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.739

GnomAD3 exomes AF: 0.689 AC: 171864 AN: 249378 Hom.: 61326 AF XY: 0.698 AC XY: 94403 AN XY: 135292

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.419

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.765

Gnomad SAS exome AF: 0.727

Gnomad FIN exome AF: 0.700

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.708 AC: 1033677 AN: 1461020 Hom.: 368824 Cov.: 41 AF XY: 0.709 AC XY: 515613 AN XY: 726866

Gnomad4 AFR exome AF: 0.892

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.761

Gnomad4 EAS exome AF: 0.783

Gnomad4 SAS exome AF: 0.732

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.747 AC: 113570 AN: 151954 Hom.: 43283 Cov.: 29 AF XY: 0.742 AC XY: 55127 AN XY: 74254

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.549

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.777

Gnomad4 SAS AF: 0.739

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.738

Alfa AF: 0.709 Hom.: 56412

Bravo AF: 0.740

Asia WGS AF: 0.735 AC: 2555 AN: 3478

EpiCase AF: 0.712

EpiControl AF: 0.719

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NOS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.8
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2293054; hg19: chr12-117701714; COSMIC: COSV57609647;